US4985444A - Pyrazolopyridine compound and processes for preparation thereof - Google Patents

Pyrazolopyridine compound and processes for preparation thereof Download PDF

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US4985444A
US4985444A US07/466,929 US46692990A US4985444A US 4985444 A US4985444 A US 4985444A US 46692990 A US46692990 A US 46692990A US 4985444 A US4985444 A US 4985444A
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alkyl
oxo
compound
carboxy
phenylpyrazolo
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Youichi Shiokawa
Atsushi Akahane
Hirohito Katayama
Takafumi Mitsunaga
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Fujisawa Pharmaceutical Co Ltd
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Fujisawa Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
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    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to novel pyrazolopyridine compound and a pharmaceutically acceptable salt thereof.
  • novel pyrazolopyridine compound and a pharmaceutically acceptable salt thereof which are adenosine antagonists and possess various pharmaceutical actions such as cognitive enhancing action, analgesic action, locomotor action, antidepressant action, cerebral vasodilating action, diuretic action, cardiotonic action, vasodilating action, the action of increasing the renal blood flow, enhanced lipolysis action, inhibited anaphylactic bronchoconstrictive action, accelerating action of the release of insulin, or the like, and so are useful as psychostimulant, analgesic, antidepressant ameliorants ofcerebral circulation, remedy for heart failure, cardiotonic agent, antihypertensive agent, remedy for renal insufficiency, diuretic, remedy for edema, antiobesity, antiasthmatic, bronchoconstrictor, remedy for apnea, remedy for gout, remedy for hyperuricemia, remedy for sudden infant death syndrome (SIDS), ameliorants of
  • edema e.g. cardiac edema, nephrotic edema, hepatic edema, idiopathic edema, drug edema, acute angioneurotic edema, hereditary angioneurotic edema, carcinomatous ascites, gestational edema, etc.
  • obesity bronchial asthma, gout, hyperuricemia, sudden infant death syndrome, immunosuppresion, diabetes, myocardiac infarction, thrombosis (e.g. arterial thrombosis, cerebral thrombosis, etc.), obstruction, arteriosclerosis obliterans, thrombophlebitis, cerebral infarction, transient ischemic attack, angina pectoris or the like.
  • one object of the present invention is to provide the novel pyrazolopyridine compound and a pharmaceutically acceptable salt thereof, which are useful as stated above.
  • Another object of the present invention is to provide processes for the preparation of the novel pyrazolopyridine compound or a salt thereof.
  • a further object of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising, as an active ingredient, said pyrazolopyridine compound or a pharmaceutically acceptable salt thereof.
  • Still further object of the present invention is to provide a method for using said pyrazolopyridine compound as aforesaid therapeutic use, which comprises administering said pyrazolopyridine compound to human being or animals.
  • novel pyrazolopyridine compound of the present invention can be shown by the following formula (I). ##STR2## wherein R 1 is aryl, and
  • R 2 is unsaturated heterocyclic group which may have one or more suitable substituent(s).
  • the object compound (I) or a salt thereof can be prepared, for example, according to the following reaction schemes. ##STR3## wherein R 1 and R 2 are each as defined above,
  • R a 2 is heterocyclic compound having ##STR4## moiety in its ring, which may have one or more suitable substituent(s)
  • R b 2 is N-containing unsaturated heterocyclic compound having ⁇ N-- moiety in its ring, which may have one or more suitable substituent(s)
  • R c 2 is N-containing unsaturated heterocyclic group, which may have one or more suitable substituent(s),
  • R d 2 is unsaturated heterocyclic group having cyano, which may have one or more suitable substituent(s),
  • R e 2 is unsaturated heterocyclic group having carboxy, which may have one or more suitable substituent(s),
  • R f 2 is unsaturated heterocyclic group which may have one or more suitable substituent(s) except carboxy,
  • R g 2 is unsaturated heterocyclic group having amino, which may have one or more suitable substituent(s),
  • R h 2 is unsaturated heterocyclic group having oxo, which may have one or more suitable substituent(s),
  • R i 2 is unsaturated heterocyclic group having halogen, which may have one or more suitable substituent(s),
  • R j 2 is unsaturated heterocyclic group having di(lower)alkylamino, which may have one or more suitable substituent(s),
  • R k 2 is unsaturated heterocyclic group having lower alkoxy, which may have one or more suitable substituent(s),
  • a group of the formula : ##STR5## is unsaturated cyclic amino group, which may have one or more suitable substituent(s),
  • R 3 is an acyl group
  • R 4 is lower alkyl which may have one or more suitable substituent(s),
  • R a 4 is protected carboxy(lower)alkyl
  • R b 4 is carboxy(lower)alkyl
  • R c 4 is amidated carboxy(lower)alkyl
  • R 5 is protected carboxy
  • R 6 is lower alkyl
  • R 7 is hydrogen or lower alkyl
  • R 8 is hydrogen, lower alkyl or amino
  • R 9 is lower alkyl
  • R 10 is protected carboxy
  • X is a leaving group
  • the compounds (VI), (X), (XII) and (XV) are novel, and they can be prepared according to the methods described in Preparations disclosed later in the present specification or similar manners thereto.
  • Suitable pharmaceutically acceptable salts of the object compound (I) are conventional ones and include a metal salt such as an alkali metal salt (e.g. sodium salt, potassium salt, etc.) and an alkaline earth metal salt (e.g. calcium salt, magnesium salt, etc.), an ammonium salt, an organic base salt (e.g. trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.), an organic acid salt (e.g.
  • a metal salt such as an alkali metal salt (e.g. sodium salt, potassium salt, etc.) and an alkaline earth metal salt (e.g. calcium salt, magnesium salt, etc.), an ammonium salt, an organic base salt (e.g. trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,N'-dibenzylethylenedi
  • an inorganic acid salt e.g. hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, etc.
  • a salt with an amino acid e.g. arginine, aspartic acid, glutamic acid, etc.
  • Suitable "aryl” may include phenyl, tolyl, xylyl, naphthyl and the like, in which the preferred one may be phenyl.
  • Suitable "unsaturated heterocyclic group” may include unsaturated, monocyclic or polycyclic heterocYclic group containing at least one hetero atom such as nitrogen, oxygen, sulfur or the like.
  • Suitable examples of said "unsaturated heterocYclic group” may include:
  • 1,2,3,6-tetrahydropyridyl, etc. pyrimidinyl, dihydropyrimidinyl (e.g. 1,2-dihydropyrimidinyl, etc.), pyrazinyl, pyridazinyl, dihydropyridazinyl (e.g. 2,3-dihydropyridazinyl, 1,4-dihydropyridazinyl, etc.), tetrahydropyridazinyl (e.g. 2,3,4,5-tetrahydropyridazinyl, etc.) triazolyl (e.g.
  • Aforesaid "unsaturated heterocyclic group” may have one or more (preferably 1 to 4) suitable substituent(s) such as lower alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl, etc.) which may have one or more (preferably 1 to 4) suitable substituent(s) as explained below; carboxy(lower)alkenyl (e.g.
  • Suitable "an acyl group” may include lower alkanoyl (e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, pivaloyl, hexanoyl, etc.), carboxy, protected carboxy, and the like.
  • lower alkanoyl e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, pivaloyl, hexanoyl, etc.
  • Suitable examples of aforesaid "protected carboxy” may be esterified carboxy, in which suitable esterified carboxy may include lower alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, etc.) and the like;
  • suitable esterified carboxy may include lower alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, etc.) and the like;
  • amidated carboxy in which suitable amidated carboxy may include carbamoyl, N,N-di(lower)alkylcarbamoyl wherein two lower alkyl groups may bond to each other to form 3 to 6-membered ring (e.g.
  • N,N-dimethylcarbamoyl N-methyl-N-ethylcarbamoyl, N,N-diethylcarbamoyl, N,N-dipropylcarbamoyl, N-butyl-N-t-butylcarbamoyl, N,N-dipentylcarbamoyl, N-pentyl-N-hexylcarbamoyl, 1-aziridinylcarbonyl, 1-azetidinylcarbonyl, 1-pyrrolidinylcarbonyl, piperidinocarbonyl, etc.) and the like; or the like.
  • Suitable examples of "suitable substituent(s)" of aforesaid "lower alkyl which may have one or more suitable substituent(s)” may include hydroxy, aforesaid halogen, aforesaid lower alkoxy, aforesaid an acyl group, and the like.
  • Suitable examples of said "lower alkyl having one or more suitable substituent(s)" may include lower alkyl having hydroxy and halogen (e.g. 1-hydroxy-1-chloromethyl, 1-hydroxy-2-chloroethyl, 2-hydroxy-3-fluoropropyl, 2-hydroxy-3,3,3-trichloropropyl, 3-bromo-4-hydroxy-4-iodobutyl, 1-chloro-2-hydroxy-4-fluoropentyl, 3,4-dihydroxy-6-chlorohexyl, etc);
  • hydroxy and halogen e.g. 1-hydroxy-1-chloromethyl, 1-hydroxy-2-chloroethyl, 2-hydroxy-3-fluoropropyl, 2-hydroxy-3,3,3-trichloropropyl, 3-bromo-4-hydroxy-4-iodobutyl, 1-chloro-2-hydroxy-4-fluoropentyl, 3,4-dihydroxy-6-chlorohexyl, etc
  • hydroxy(lower)alkyl e.g. hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-hydroxy-1-methylethyl, 1-hydroxybutyl, 1-hydroxymethyl-1-methylethyl, 3-hydroxypentyl, 2-hydroxyhexyl, etc.
  • lower alkoxy(lower)alkyl e.g. methoxymethyl, ethoxymethyl, 2-ethoxyethyl, 1-propoxyethyl, 3-isopropoxypropyl, 2-butoxybutyl, 1-t-butoxymethyl-1-methylethyl, 5-pentyloxypentyl, hexyloxymethyl, 3-hexyloxyhexyl, etc.
  • lower alkoxy(lower)alkyl e.g. methoxymethyl, ethoxymethyl, 2-ethoxyethyl, 1-propoxyethyl, 3-isopropoxypropyl, 2-butoxybutyl, 1-t-butoxymethyl-1-methylethyl, 5-pentyloxypentyl, hexyloxymethyl, 3-hexyloxyhexyl, etc.
  • acyl(lower)alkyl in which the preferred one may be carboxy(lower)alkyl (e.g. carboxymethyl, 2-carboxyethyl, 2-carboxypropyl, 3-carboxypropyl, 2-carboxy-1-methylethyl, 4-carboxybutyl, 1-carboxymethyl-1-methylethyl, 3-carboxypentyl, 2-carboxyhexyl, etc.), and protected carboxy(lower)alkyl, in which the preferred one may be esterified carboxy(lower)alkyl and amidated carboxy(lower)alkyl, the more preferred one may be lower alkoxycarbonyl(lower)alkyl (e.g.
  • N,N-dimethylcarbamoylmethyl 2-(N,N-dimethylcarbamoyl)ethyl, 2-(N-methyl-N-ethylcarbamoyl)ethyl, 3-(N-methyl-N-ethylcarbamoyl)propyl, 2-(N,N-dipropylcarbamoyl)-1-methylethyl, 4-(N,N-dipropylcarbamoyl)butyl, 1-(N,N-dimethylcarbamoyl)methyl-1-methylethyl, 5-(N-pentyl-N-hexylcarbamoyl)pentyl, 3-(N-pentyl-N-hexyl)hexyl, (1-aziridinylcarbonyl)methyl, 2-(1-azetidinylcarbonyl)ethyl, 2-(piperidinocarbonyl)ethyl, 3-(
  • the preferred substituent of "unsaturated heterocyclic group” may be lower alkyl, lower alkyl having hydroxy and halogen, hydroxy(lower)alkyl, lower alkoxy(lower)alkyl, carboxy(lower)alkyl, lower alkoxycarbonyl(lower)alkyl, carbamoyl(lower)alkyl, N,N-di(lower)alkylcarbamoyl(lower)alkyl wherein two lower alkyl groups on nitrogen atom may bond to each other to form 3 to 6-membered ring, carboxy(lower)alkenyl, di(lower)alkylamino, halogen, lower alkoxy, oxo, carboxy, lower alkoxycarbonyl, lower alkanoyl, amino, cyano and hydroxy,
  • the more preferred one may be (C 1 -C 4 )alkyl, (C 1 -C 4 )alkyl having hydroxy and halogen, hydroxy(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy(C 1 -C 4 )alkyl, carboxy(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxycarbonyl(C 1 -C 4 )alkyl, carbamoyl(C 1 -C 4 )alkyl, N,N-di(C 1 -C 4 )alkylcarbamoyl(C 1 -C 4 )alkyl, piperidinocarbonyl(C 1 -C 4 )alkyl, carboxy(C 2 -C 4 )alkenyl, di(C 1 -C 4 )alkylamino, halogen, (C 1 -C 4 )alkoxy, oxo, carboxy(
  • Suitable "heterocyclic compound having ##STR6## moiety in its ring” may include saturated or unsaturated, monocyclic or polycyclic heterocyclic compound containing at least one hetero atom such as nitrogen, oxygen, sulfur or the like, which has ##STR7## moiety in its ring, and suitable examples thereof may include:
  • azepine having oxo e.g. 2-oxo-2H-azepine, etc.
  • pyrrole having oxo e.g. 5-oxopyrroline, etc.
  • pyrroline having oxo e.g. 2-oxopyrrolidine, etc.
  • imidazole having oxo e.g. 4-oxoimidazoline, etc.
  • pyrazole having oxo e.g.
  • 5-oxopyrazoline, etc. pyridine having oxo (e.g. 4-oxo-1,4-dihydropyridine, etc.), dihydropyridine having oxo (e.g. 2-oxo-1,2,3,4-tetrahydropyridine, 4-oxo-1,2,3,4-tetrahydropyridine, etc.), tetrahydropyridine having oxo (e.g. 2-oxopiperidine, 4-oxopiperidine, etc.), pyrimidine having oxo (e.g. 2-oxo-1,2-dihydropyrimidine, etc.), dihydropyrimidine having oxo (e.g.
  • 3-oxo-perhydropyridazine, etc. triazole having oxo (e.g. 3-oxo-2,3-dihydro-4H-1,2,4-triazole, 4-oxo-4,5-dihydro-1H-1,2,3-triazole, 5-oxo-1,5-dihydro-2H-1,2,3-triazole, etc.), tetrazole having oxo (e.g. 5-oxo-4,5-dihydro-1H-tetrazole, 5-oxo-1,5-dihydro-2H-tetrazole, etc.), etc.;
  • indole having oxo e.g. 2-oxo-2,3-dihydroindole, etc.
  • isoindole having oxo e.g. 7-oxo-6,7-dihydroisoindole, etc.
  • indolizine having oxo e.g. 3-oxo-2,3-dihydroindolizine, etc.
  • benzimidazole having oxo e.g.
  • 2-oxo-2,3-dihydro-1H-benzimidazole, etc. 2-oxo-2,3-dihydro-1H-benzimidazole, etc.
  • quinoline having oxo e.g. 4-oxo-3,4-dihydroquinoline, etc.
  • dihydroquinoline having oxo e.g. 5-oxo-1,4,5,6-tetrahydroquinoline, etc.
  • isoquinoline having oxo e.g. 4-oxo-3,4-dihydroisoquinoline, etc.
  • indazole having oxo e.g. 3-oxo-2,3-dihydro-1H-indazole, etc.
  • benzotriazole having oxo e.g. 4-oxo-4,5-dihydro-1H-benzotriazole, etc.
  • oxazole having (e.g. 4-oxo-4,5-dihydroxazole, etc.), isoxazole having oxo (e.g. 3-oxo-2,3-dihydroisoxazole, etc.), dihydroisoxazole having oxo (e.g. 4-oxo-isoxazolidine, etc.), oxadiazole having oxo (e.g. 3-oxo-2,3-dihydro-1,2,4-oxadiazole, 3-oxo-2,3-dihydro-1,2,5-oxadiazole, etc.), etc.;
  • thiazole having oxo e.g. 4-oxo-4,5-dihydrothiazole, etc.
  • dihydrothiazole having oxo e.g. 4-oxo-thiazolidine, etc.
  • isothiazole having oxo e.g. 3-oxo-2,3-dihydroisothiazole, etc.
  • thiadiazole having oxo e.g.
  • benzothiazole having oxo e.g. 2-oxo-2,3-dihydrobenzothiazole, etc.
  • benzothiadiazole having oxo e.g. 6-oxo-6,7-dihydrobenzothiadiazole, etc.
  • imidazothiadiazole having oxo e.g. 5-oxo-5H-imidazo[2,1-b][1,3,4]thiadiazole, etc.
  • heterocyclic compound having ##STR19## moiety in its ring may have one or more (preferably 1 to 4) suitable substituent(s) as exemplified above for "suitable substituent(s)" of "unsaturated heterocyclic group".
  • Suitable "N-containing unsaturated heterocyclic compound having ⁇ N-- moiety in its ring” may be heterocyclic compound containing at least one nitrogen atom and also containing at least one ⁇ N-- moiety in its ring.
  • Suitable example of said "N-containing unsaturated heterocyclic compound having ⁇ N-- moiety in its ring” may include:
  • unsaturated 3 to 8-membered (more preferably 5 to 7-membered) heteromonocyclic compound containing 1 to 4 nitrogen atom(s) having ⁇ N-- moiety in its ring for example, azepine (e.g. 1H-azepine, etc.) imidazole, pyrazole, pyridine, dihydropyridine (e.g. 3,4-dihydropyridine, 5,6-dihydropyridine, etc.), tetrahydropyridine (e.g. 3,4,5,6-tetrahydropyridine, etc.) pyrimidine, dihydropyrimidine (e.g.
  • 1,2-dihydropyrimidine, etc pyrazine, pyridazine, dihydropyridazine (e.g. 2,3-dihydropyridazine, 1,4-dihydropyridazine, etc.), tetrahydropyridazine (e.g. 2,3,4,5-tetrahydropyridazine, etc.), triazole (e.g. 4H-1,2,4-triazole, 1H-1,2,3-triazole, 2H-1,2,3-triazole, etc.), tetrazole (e.g. 1H-tetrazole, 2H-tetrazole, etc.), etc.;
  • unsaturated condensed heterocyclic compound containing 1 to 4 nitrogen atom(s) having ⁇ N-- moiety in its ring for example, indole, benzimidazole, quinoline dihydroquinoline (e.g. 3,4-dihydroquinoline, etc.) isoquinoline, indazole, benzotriazole, etc.;
  • unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic compound containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s) having ⁇ N-- moiety in its ring for example, oxazole, isoxazole, dihydroisoxazole (e.g. 4,5-dihydroisoxazole, etc.) oxadiazole (e.g. 1,2,4-oxadiazole, 1,3,4-oxadiazole, 1,2,5-oxadiazole, etc.), etc.;
  • unsaturated condensed heterocyclic compound containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), having ⁇ N-- moiety in its ring for example, benzoxazole, benzoxadiazole, etc.;
  • unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic compound containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s) having ⁇ N-- moiety in its ring for example, thiazole, dihydrothiazole (e.g. 4,5-dihydrothiazole, etc.) isothiazole, thiadiazole (e.g. 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, 1,2,5-thiadiazole, etc.), dihydrothiazine, etc.;
  • unsaturated condensed heterocyclic compound containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s) having ⁇ N-- moiety in its ring for example, benzothiazole, benzothiadiazole, imidazothiadiazole, etc.
  • N-containing unsaturated heterocyclic compound having ⁇ N-- moiety in its ring may have one or more (preferably 1 to 4) suitable substituent(s) as exemplified above for "suitable substituent(s)" of "unsaturated heterocyclic group".
  • Suitable "N-containing unsaturated heterocyclic group” may be unsaturated heterocyclic group containing at least one nitrogen atom as hetero atom and suitable examples thereof can be referred to unsaturated heterocyclic group containing at least one nitrogen atom as exemplified for "unsaturated heterocyclic group" before.
  • N-containing unsaturated heterocyclic group may have one or more (preferably 1 to 4) suitable substituent(s) as exemplified above for "suitable substituent(s)" of "unsaturated heterocyclic group".
  • Suitable “unsaturated heterocyclic group having cyano” may be “unsaturated heterocyclic group” as explained above which has cyano as its substituent, and said "unsaturated heterocyclic group having cyano” may have additionally one or more (preferably 1 to 4) suitable substituent(s) as exemplified above for "suitable substituent(s)" of "unsaturated heterocyclic group".
  • Suitable “unsaturated heterocyclic group having carboxy” may be “unsaturated heterocyclic group” as explained above which has carboxy as its substituent, and said "unsaturated heterocyclic group having carboxy” may have additionally one or more (preferably 1 to 4) suitable substituent(s) as exemplified above for "suitable substituent(s)" of "unsaturated heterocyclic group".
  • Suitable “unsaturated heterocyclic group having amino” may be “unsaturated heterocyclic group” as explained above which has amino as its substituent, and said "unsaturated heterocyclic group having amino” may have additionally one or more (preferably 1 to 4) suitable substituent(s) as exemplified above for "suitable substituent(s)" of "unsaturated heterocyclic group".
  • Suitable “unsaturated heterocyclic group having oxo” may be “unsaturated heterocyclic group” as explained above which has oxo as its substituent, and said "unsaturated heterocyclic group having oxo” may have additionally one or more (preferably 1 to 4) suitable substituent(s) as exemplified above for "suitable substituent(s)" of "unsaturated heterocyclic group".
  • Suitable “unsaturated heterocyclic group having halogen” may be “unsaturated heterocyclic group” as explained above which has halogen as its substituent, and said "unsaturated heterocyclic group having halogen” may have additionally one or more (preferably 1 to 4) suitable substituent(s) as exemplified above for "suitable substituent(s)" of "unsaturated heterocyclic group".
  • Suitable “unsaturated heterocyclic group having di(lower)alkylamino” may be “unsaturated heterocyclic group” as explained above which has di(lower)alkylamino as its substituent, and said "unsaturated heterocyclic group having di(lower)alkylamino” may have additionally one or more (preferably 1 to 4) suitable substituent(s) as exemplified above for "suitable substituent(s)" of "unsaturated heterocyclic group”.
  • Suitable “unsaturated heterocyclic group having lower alkoxy” may be “unsaturated heterocyclic group” as explained above which has lower alkoxy as its substituent, and said "unsaturated heterocyclic group having lower alkoxy” may have additionally one or more (preferably 1 to 4) suitable substituent(s) as exemplified above for "suitable substituent(s)" of "unsaturated heterocyclic group".
  • Suitable "unsaturated heterocyclic group which may have one or more suitable substituent(s) except carboxy” may be “unsaturated heterocyclic group” as explained above which may have one or more (preferably 1 to 4) suitable substituent(s), as exemplified for "suitable substituent(s)" of "unsaturated heterocyclic group", except carboxy.
  • Suitable "unsaturated cyclic amino group” may include unsaturated, monocyclic or polycyclic amino group which may contain additional hetero atom such as nitrogen, oxygen, sulfur or the like.
  • Suitable examples of said "unsaturated cyclic amino group” may include:
  • azepin-1-yl e.g. 1H-azepin-1-yl, etc.
  • 1-pyrrolyl 1-pyrrolinyl, 1-imidazolyl, 1-pyrazolyl, dihydropyridin-1-yl (e.g. 1,2-dihydropyridin-1-yl, 1,4-dihydropyridin-1-yl, etc.), tetrahydropyridyl (e.g.
  • dihydropyrimidinyl e.g. 1,2-dihydropyrimidin-1-yl, etc.
  • dihydropyridazinyl e.g. 2,3-dihydropyridazin-2-yl, 1,4-dihydropyridazin-1-yl, etc.
  • tetrahydropyridazinyl e.g. 2,3,4,5-tetrahydropyridazin-2-yl, etc.
  • triazolyl e.g.
  • dihydroxazolyl e.g. 2,3-dihydroxazol-3-yl, etc.
  • dihydroisoxazolyl e.g. 2,5-dihydroisoxazol-2-yl, etc.
  • Aforesaid "unsaturated cyclic amino group” may have one or more (preferably 1 to 4) suitable substituent(s) as exemplified above for "suitable substituent(s) of "unsaturated heterocyclic group".
  • Suitable “a leaving group” may include di(lower)alkylamino (e.g. dimethylamino, diethylamino, N-ethylpropylamino, dibutylamino, N-pentylhexylamino, etc.), lower alkoxy as mentioned above, halogen as mentioned above, lower alkylthio (e.g. methylthio, ethylthio, propylthio, butylthio, pentylthio, hexylthio, etc.), acyloxy such as lower alkanoyloxy (e.g. acetoxy, etc.), sulfonyloxy (e.g. mesyloxy, tosyloxy, etc.) or the like, and the like.
  • di(lower)alkylamino e.g. dimethylamino, diethylamino, N-ethylpropylamino, dibutylamino, N-
  • the object compound (I) or a salt thereof can be prepared by reacting the compound (II) or a salt thereof with the compound (III) or a salt thereof.
  • Suitable salt of the compound (II) can be referred to acid addition salt as exemplified for the compound (I).
  • Suitable salt of the compound (III) can be referred to the ones as exemplified for the compound (I).
  • This reaction is preferably carried out in a solvent such as acetic acid, benzene, pyridine or any other solvent which does not adversely affect the reaction.
  • This reaction may be carried out in the presence of an acid such as sulfuric acid, hydrochloric acid, p-toluenesulfonic acid or the like.
  • an acid such as sulfuric acid, hydrochloric acid, p-toluenesulfonic acid or the like.
  • the reaction temperature is not critical and the reaction is usually carried out under warming to heating.
  • the object compound (Ia) or a salt thereof can be prepared by reacting the compound (II) or a salt thereof with the compound (IV) or a salt thereof.
  • Suitable salt of the compound (Ia) can be referred to the ones as exemplified for the compound (I).
  • Suitable salt of the compound (II) can be referred to an acid addition salt as exemplified for the compound (I).
  • Suitable salt of the compound (IV) can be referred to the ones as exemplified for the compound (I).
  • the group R 3 i.e. an acyl group
  • an acylating agent such as lower alkyl haloformate (e.g. methyl chloroformate, ethyl chloroformate, etc.), acid halide (e.g. acetyl chloride, propionyl bromide, etc.).
  • This reaction is usually carried out in a solvent such as methylene chloride, chloroform, tetrahydrofuran, N,N-dimethylformamide or any other solvent which does not adversely influence the reaction.
  • a solvent such as methylene chloride, chloroform, tetrahydrofuran, N,N-dimethylformamide or any other solvent which does not adversely influence the reaction.
  • the reaction temperature is not critical and the reaction is usually carried out at room temperature, under warming to heating.
  • the object compound (Ib) or a salt thereof can be prepared by subjecting the compound (Ia) or a salt thereof to removal reaction of an acyl group.
  • Suitable salt of the compound (Ib) can be referred to the ones as exemplified for the compound (I).
  • the removal reaction of this process can be carried out in the dehydrogenation condition (e.g. potassium t-butoxide in t-butanol, manganese oxide in chloroform , etc.), conventional hydrolysis condition (e.g. alkali metal hydroxide (e.g. sodium hydroxide, potassium hydroxide, etc.) in alcohol (e.g. methanol, ethanol, etc.) and water; or the like.
  • dehydrogenation condition e.g. potassium t-butoxide in t-butanol, manganese oxide in chloroform , etc.
  • conventional hydrolysis condition e.g. alkali metal hydroxide (e.g. sodium hydroxide, potassium hydroxide, etc.) in alcohol (e.g. methanol, ethanol, etc.) and water; or the like.
  • the reaction condition can be selected according to the kind of the compound (Ia) to be used.
  • the reaction temperature is not critical and the reaction is usually carried out at room temperature, under warming to heating.
  • the object compound (Id) or a salt thereof can be prepared by subjecting the compound (Ic) or a salt thereof to introduction reaction of lower alkyl which may have one or more suitable substituent(s).
  • Suitable salt of the compound (Id) can be referred to the ones as exemplified for the compound (I).
  • the introduction reaction of this process can be carried out by reacting the compound (Ic) or a salt thereof with a reagent for introduction of lower alkyl which may have one or more suitable substituent(s).
  • Suitable reagent for introduction of lower alkyl which may have one or more suitable substituent(s) can include a compound of the formula:
  • R 4 is as defined above and X is a leaving group such as an acyloxy [e.g. lower alkanoyloxy (e.g. formyloxy, acetoxy, propionyloxy, butyryloxy, pivaloyloxy, hexanoyloxy, etc.), sulfonyloxy (e.g. mesyloxy, tosyloxy, etc.), etc.], halogen (e.g. fluoro, chloro, bromo, iodo) or the like]; acyl(lower)alkene in which the double bond is adjacent to acyl group such as acrylic acid and its derivative (e.g. methyl acrylate, ethyl acrylate, etc.), crotonic acid and its derivative (e.g. methyl crotonate, ethyl crotonate, etc.); and the like.
  • acyloxy e.g. lower alkanoyloxy (e.g. for
  • This reaction is usually carried out in a solvent such as diethyl ether, chloroform, methylene chloride, N,N-dimethylformamide, alcohol (e.g. methanol, ethanol, etc.) or any other solvent which does not adversely influence the reaction.
  • a solvent such as diethyl ether, chloroform, methylene chloride, N,N-dimethylformamide, alcohol (e.g. methanol, ethanol, etc.) or any other solvent which does not adversely influence the reaction.
  • the reaction temperature is not critical and the reaction is usually carried out under cooling, at room temperature, under warming to heating.
  • the reaction can be carried out in the presence of condensation catalyst (e.g. trimethylbenzylammonium hydroxide, etc.).
  • condensation catalyst e.g. trimethylbenzylammonium hydroxide, etc.
  • the object compound (If) or a salt thereof can be prepared by subjecting the compound (Ie) or a salt thereof to removal reaction of carboxy protective group.
  • Suitable salts of the compounds (Ie) and (If) can be referred to the ones as exemplified for the compound (I).
  • This reaction is carried out in accordance with a conventional method such as hydrolysis or the like.
  • the hydrolysis is preferably carried out in the presence of a base or an acid including Lewis acid.
  • Suitable base may include an inorganic base and an organic base such as an alkali metal [e.g. sodium, potassium, etc.], an alkaline earth metal [e.g. magnesium, calcium, etc.], the hydroxide or carbonate or bicarbonate thereof, trialkylamine [e.g. trimethylamine, triethylamine, etc.],picoline, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]undec-7-ene, or the like.
  • an alkali metal e.g. sodium, potassium, etc.
  • an alkaline earth metal e.g. magnesium, calcium, etc.
  • trialkylamine e.g. trimethylamine, triethylamine, etc.
  • picoline 1,5-diazabicyclo[4.3.0]non-5-ene
  • Suitable acid may include an organic acid [e.g. formic acid,.acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.] and an inorganic acid [e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, etc.].
  • organic acid e.g. formic acid,.acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.
  • an inorganic acid e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, etc.
  • Lewis acid such as trihaloacetic acid [e.g. trichloroacetic acid, trifluoroacetic acid, etc.] or the like is preferably carried out in the presence of cation trapping agents [e.g. anisole, phenol, etc.].
  • the reaction is usually carried out in a solvent such as water, an alcohol [e.g. methanol, ethanol, etc.], methylene chloride, tetrahydrofuran, a mixture thereof or any other solvent which does not adversely influence the reaction.
  • a solvent such as water, an alcohol [e.g. methanol, ethanol, etc.], methylene chloride, tetrahydrofuran, a mixture thereof or any other solvent which does not adversely influence the reaction.
  • a liquid base or acid can be also used as the solvent.
  • the reaction temperature is not critical and the reaction is usually carried out under cooling to warming.
  • the object compound (Ig) or a salt thereof can be prepared by subjecting the compound (V) or a salt thereof to formation reaction of pyridazinone ring.
  • Suitable salts of the compounds (Ig) and (V) can be referred to acid addition salts as exemplified for the compound (I).
  • the formation reaction of this process can be carried out, for example, by reacting the compound (V) or a salt thereof with glyoxalic acid or its reactive derivative or a salt thereof and hydrazine or a salt thereof.
  • Suitable salt of glyoxalic acid can be referred to a salt with a base as exemplified for the compound (I).
  • Suitable salt of hydrazine can be referred to an acid addition salt as exemplified for the compound (I).
  • Suitable reactive derivative of glyoxalic acid may be the ones conventionally used in this field of the art such as an activated ester thereof.
  • the reaction can be carried out in the presence or absence of a solvent.
  • the reaction temperature is not critical and the reaction is usually carried out under warming to heating.
  • the object compound (Ih) or a salt thereof can be prepared by reacting the compound (VI) or a salt thereof with the compound (VII) or a salt thereof.
  • Suitable salts of the compounds (Ih), (VI) and (VII) can be referred to acid addition salt as exemplified for the compound (I).
  • This reaction can be carried out, for example, according to the procedure as disclosed in Example 15.
  • the object compound (Ii) or a salt thereof can be prepared by reacting the compound (VIII) or a salt thereof with the compound (IX) or its reactive derivative at methyl group or a salt thereof.
  • Suitable salts of the compounds (Ii), (VIII) and (IX) can be referred to acid addition salt as exemplified for the compound (I).
  • Suitable reactive derivative at methyl group of the compound (IX) may be its pyridinium derivative or the like.
  • the object compound (Ij) or a salt thereof can be prepared by reacting the compound (X) or a salt thereof with the compound (XI) or a salt thereof.
  • Suitable salt of the compound (Ij), (X) and (XI) can be referred to acid addition salt as exemplified for the compound (I).
  • This reaction can be carried out, for example, according to the procedure as disclosed in Example 17.
  • the object compound (Ik) or a salt thereof can be prepared by reacting the compound (XII) or a salt thereof with the compound (XI) or a salt thereof.
  • Suitable salt of the compound (Ik), (XII) and (XI) can be referred to acid addition salt as exemplified for the compound (I).
  • This reaction can be carried out, for example, according to the procedure as disclosed in Example 18.
  • the object compound (Il) or a salt thereof can be prepared by reacting the compound (XIII) or a salt thereof with the compound (XIV) or a salt thereof.
  • Suitable salt of the compounds (Il), (XIII) and (XIV) can be referred to acid addition salt as exemplified for the compound (I).
  • This reaction can be carried out, for example, according to the procedure as disclosed in Example 19.
  • the object compound (Im) or a salt thereof can be prepared by reacting the compound (XV) or a salt thereof with the compound (XVI) or a salt thereof.
  • Suitable salt of the compounds (Im), (XV) and (XVI) can be referred to acid addition salt as exemplified for the compound (I).
  • This reaction can be carried out, for example, according to the procedure as disclosed in Example 20.
  • the object compound (In) or a salt thereof can be prepared by reacting the compound (XV) or a salt thereof with the compound (XVII) or a salt thereof.
  • Suitable salt of the compounds (In), (XV) and (XVII) can be referred to acid addition salt as exemplified for the compound (I).
  • This reaction can be carried out, for example, according to the procedure as disclosed in Example 21.
  • the object compound (Io) or a salt thereof can be prepared by reacting the compound (XV) or a salt thereof with the compound (XVIII) or a salt thereof.
  • Suitable salt of the compounds (Io), (XV) and (XVIII) can be referred to acid addition salt as exemplified for the compound (I).
  • This reaction can be carried out, for example, according to the procedure as disclosed in Example 23.
  • the object compound (Iq) or a salt thereof can be prepared by subjecting the compound (Ip) or a salt thereof to hydrolysis reaction of cyano group.
  • Suitable salts of the compounds, (Ip) and (Iq) can be referred to the ones as exemplified for the compound (I).
  • This hydrolysis reaction can be carried out according to a similar manner to that disclosed in the explanation of Process 5.
  • the object compound (Ir) or a salt thereof can be prepared by subjecting the compound (Iq) or a salt thereof to removal reaction of carboxy group.
  • Suitable salts of the compounds (Iq) and (Ir) can be referred to the ones as exemplified for the compound (I).
  • This reaction can be carried out, for example, according to the procedure as disclosed in Example 45.
  • the object compound (Is) or a salt thereof can be prepared by subjecting the compound (If) or a salt thereof to amidation reaction.
  • Suitable salts of the compounds (If) and (Is) can be referred to the ones as exemplified for the compound (I).
  • This reaction can be carried out by reacting the compound (If) or a salt thereof with an amidation reagent such as ammonia, di(lower)alkylamine wherein two lower alkyl groups may bond to each other to form 3 to 6-membered ring (e.g. dimethylamine, N-methylethylamine, diethylamine, dipropylamine, N-butyl-t-butylamine, dipentylamine, N-pentylhexylamine, aziridine, azetidine, pyrrolidine, piperidine, etc.) or the like.
  • an amidation reagent such as ammonia, di(lower)alkylamine wherein two lower alkyl groups may bond to each other to form 3 to 6-membered ring (e.g. dimethylamine, N-methylethylamine, diethylamine, dipropylamine, N-butyl-t-butylamine, dipentylamine, N-pentylhex
  • the reaction is usually carried out in a conventional solvent such as water, alcohol [e.g. methanol, ethanol, etc.], acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or any other organic solvent which does not adversely influence the reaction.
  • a conventional solvent such as water, alcohol [e.g. methanol, ethanol, etc.], acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or any other organic solvent which does not adversely influence the reaction.
  • a conventional solvent such as water, alcohol [e.g. methanol, ethanol, etc.], acetone, dioxane, acetonitrile,
  • reaction when the compound (If) is used in a free acid form or its salt form, the reaction is preferably carried out in the presence of a conventional condensing agent such as N,N'-dicyclohexylcarbodiimide; or the like.
  • a conventional condensing agent such as N,N'-dicyclohexylcarbodiimide; or the like.
  • the reaction may also be carried out in the presence of an inorganic or organic base such as an alkali metal carbonate, alkali metal bicarbonate, tri(lower)alkylamine (e.g. triethylamine, etc.), pyridine N-(lower)alkylmorpholine, N,N-di(lower)alkylbenzylamine, or the like.
  • an inorganic or organic base such as an alkali metal carbonate, alkali metal bicarbonate, tri(lower)alkylamine (e.g. triethylamine, etc.), pyridine N-(lower)alkylmorpholine, N,N-di(lower)alkylbenzylamine, or the like.
  • the reaction temperature is not critical, and the reaction is usually carried out under cooling to warming.
  • the object compound (Iu) or a salt thereof can be prepared by subjecting the compound (It) or a salt thereof to conversion reaction of amino group to oxo group.
  • Suitable salts of the compounds (It) and (Iu) can be referred to the ones as exemplified for the compound (I).
  • This reaction can be carried out, for example, according to the procedure as disclosed in Example 52.
  • the object compound (Iv) or a salt thereof can be prepared by subjecting the compound (Iu) or a salt thereof to removal reaction of carboxy group.
  • Suitable salt of the compounds (Iu) and (Iv) can be referred to the ones as exemplified for the compound (I).
  • This reaction can be carried out, for example, according to the procedure as disclosed in Example 54.
  • the object compound (Iw) or a salt thereof can be prepared by reacting the compound (Iv) or a salt thereof with the compound (XIX) or a salt thereof.
  • Suitable salts of the compounds (Iv) and (Iw) can be referred to the ones as exemplified for the compound (I).
  • Suitable salt of the compound (XIX) can be referred to acid addition salt as exemplified for the compound (I).
  • This reaction can be carried out, for example, according to the procedure as disclosed in Example 57.
  • the object compound (Ix) or a salt thereof can be prepared by subjecting the compound (Iv) or a salt thereof to conversion reaction of halogen to lower alkoxy.
  • Suitable salt of the compounds (Iv) and (Ix) can be referred to the ones as exemplified for the compound (I).
  • This reaction can be carried out, for example, according to the procedure as disclosed in Example 58.
  • the object compound (Iu) or a salt thereof can be prepared bY subjecting the compound (Ix) or a salt thereof to conversion reaction of lower alkoxy to oxo group.
  • Suitable salt of the compounds (Iu) and (Ix) can be referred to the ones as exemplified for the compound (I).
  • This reaction can be carried out, for example, according to the procedure as disclosed in Example 62.
  • the object compound (Iy) or a salt thereof can be prepared by reacting the compound (XX) or a salt thereof with the compound (XXI) and ammonia.
  • Suitable salts of the compounds (Iy) and (XX) can be referred to acid addition salt as exemplified for the compound (I).
  • This reaction can be carried out, for example, according to the procedure as disclosed in Example 99.
  • the object compound (I) and a salt thereof possess various actions as stated above and useful as stated before.
  • the object compound (I) and a salt thereof have high solubility into water and are advantageous in preparing a pharmaceutical preparation.
  • test results on diuretic activity of the representative compounds of the present invention are shown in the following.
  • ED 100 value (mg/kg) was as follows.
  • the object compound (I) and a pharmaceutically acceptable salt thereof of the present invention are used in the form of conventional pharmaceutical preparation which contains said compound as an active ingredient, in admixture with pharmaceutically acceptable carriers such as an organic or inorganic solid or liquid excipient which is suitable for oral, parenteral and external administration.
  • pharmaceutically acceptable carriers such as an organic or inorganic solid or liquid excipient which is suitable for oral, parenteral and external administration.
  • the pharmaceutical preparations may be in solid form such as tablet, granule, powder, capsule, or liquid form such as solution, suspension, syrup, emulsion, lemonade and the like.
  • auxiliary substances stabilizing agents, wetting agents and other commonly used additives such as lactose, citric acid, tartaric acid, stearic acid, magnesium stearate, terra alba, sucrose, corn starch, talc, gelatin, agar, pectin, peanut oil, olive oil, cacao butter, ethylene glycol, and the like.
  • the dosage of the compound (I) may vary from and also depend upon the age, conditions of the patient, a kind of diseases, a kind of the compound (I) to be applied, etc. In general, amounts between 1 mg and about 1,000 mg or even more per day may be administered to a patient. An average single dose of about 1 mg, 5 mg, 10 mg, 20 mg of the object compound (I) of the present invention may be used as diuretic and antihypertensive agent.
  • Ethyl chloroformate (3.38 g) was added dropwise with stirring to a solution of 2-phenylpyrazolo[1,5-a]pyridine (2.54 g) and pYridazine (5.00 g) in methylene chloride (5.0 ml) at 10° C. After being stirred at 10° C. for 1 hour and then at room temperature for 2 hours, the reaction mixture was poured onto ice-water (100 ml) and extracted with ethyl acetate. The combined extracts were washed with saturated sodium chloride aqueous solution (100 ml), dried over magnesium sulfate and evaporated in vacuo.
  • Example 9 The following compounds (Examples 9 and 10) were obtained according to a similar manner to that of Example 8.
  • Example 12 The following compounds (Examples 12 and 13) were obtained according to a similar manner to that of Example 11.
  • Example 22 The following compounds (Examples 22 to 25) were obtained according to a similar manner to that of Example 21.
  • Example 27 The following compounds (Examples 27 to 32) were obtained according to a similar manner to that of Example 26.
  • Example 50 The following compounds (Examples 50 and 51) were obtained according to a similar manner to that of Example 49.
  • Example 59 The following compounds (Examples 59 and 60) were obtained according to a similar manner to that of Example 58.
  • Example 66 to 74 were prepared according to similar manners to those of Example 1 and Example 2.
  • Example 75 to 89 The following compounds (Example 75 to 89) were prepared according to a similar manner to that of Example 5.
  • Example 90 The following compounds (Examples 90 to 92) were obtained according to a similar manner to that of Example 6.
  • Example 94 to 97 were obtained according to a similar manner to that of Example 5.

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US5155114A (en) * 1989-01-23 1992-10-13 Fujisawa Pharmaceutical Company, Ltd. Method of treatment using pyrazolopyridine compound
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US5338743A (en) * 1988-06-06 1994-08-16 Fujisawa Pharmaceutical Co., Ltd. New use of the adenosine antagonist
US5155114A (en) * 1989-01-23 1992-10-13 Fujisawa Pharmaceutical Company, Ltd. Method of treatment using pyrazolopyridine compound
US5204346A (en) * 1990-07-18 1993-04-20 Fujisawa Pharmaceutical Co., Ltd. Pyrazolopyridine compounds
US6355640B1 (en) * 1993-12-29 2002-03-12 Fujisawa Pharmaceutical Co., Ltd. Pyrazolopyridine adenosine antagonists
US5773530A (en) * 1993-12-29 1998-06-30 Fujisawa Pharmaceutical Co., Ltd. Pyrazolopyridine adenosine antagonists
KR100517397B1 (ko) * 1996-10-04 2005-09-29 교린 세이야꾸 가부시키 가이샤 피라졸로피리딜피리다지논 유도체 및 이를 포함하는 기관지 확장제
US6303624B1 (en) 1997-03-18 2001-10-16 Fujisawa Pharmaceutical Co., Ltd. Preventives and remedies for hyperphosphatemia
US6451794B1 (en) 1997-09-05 2002-09-17 Smithkline Beecham Corporation 2,3-Diaryl-pyrazolo[1,5-b]pyridazines derivatives, their preparation and their use as cyclooxygenase 2(COX-2) inhibitors
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US6673929B2 (en) 1999-02-26 2004-01-06 Pfizer Inc. Process for preparing growth hormone secretagogues
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US20040053942A1 (en) * 2000-08-22 2004-03-18 Alberti Michael John Fused pyrazole derivatives bieng protein kinase inhibitors
US20040110763A1 (en) * 2000-08-28 2004-06-10 Atsushi Akahane Pyrazolopyridine compound and pharmaceutical use thereof
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US20050171133A1 (en) * 2000-12-15 2005-08-04 Chamberlain Stanley D. Therapeutic compounds
US20050182080A1 (en) * 2000-12-15 2005-08-18 Chamberlain Stanley D. Therapeutic compounds
US7153855B2 (en) 2001-03-08 2006-12-26 Smithkline Beecham Corporation Pyrazolopyridinyl pyrimidine therapeutic compounds
US20060293344A1 (en) * 2001-03-08 2006-12-28 Boyd F L Therapeutic Compounds
US20050049260A1 (en) * 2001-03-08 2005-03-03 Boyd F. Leslie Therapeutic compounds
US20050107400A1 (en) * 2001-03-30 2005-05-19 Boyd Leslie F. Use of pyrazolopyridines as therapeutic compounds
US7034030B2 (en) 2001-03-30 2006-04-25 Smithkline Beecham Corporation Pyralopyridines, process for their preparation and use as therapeutic compounds
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US20060058319A1 (en) * 2001-03-30 2006-03-16 Alberti Michael J Pyrazolopyridines, process for their preparation and use as therapeutic compounds
US20060235043A1 (en) * 2001-04-10 2006-10-19 Mui Cheung Antiviral Pyrazolopyridine Compounds
US7141569B2 (en) 2001-04-10 2006-11-28 Smithkline Beecham Corporation Antiviral pyrazolopyridine compounds
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US20050192295A1 (en) * 2001-04-27 2005-09-01 Kristjan Gudmundsson Pyrazolopyridinyl pyridine and pyrimidine therapeutic compounds
US20050192303A1 (en) * 2001-04-27 2005-09-01 Kristjan Gudmundsson Pyrazolopyridinyl pyridine and pyrimidine therapeutic compounds
US20040142941A1 (en) * 2001-04-27 2004-07-22 Kristjan Gudmundsson Therapeutic compounds
US7030121B2 (en) 2001-06-06 2006-04-18 Astellas Pharma Inc. Pyrazolopyrazine compound and pharmaceutical use thereof
US20040152706A1 (en) * 2001-06-06 2004-08-05 Atsushi Akahane Pyrazolopyrazine compound pharmaceutical use thereof
US20060167252A1 (en) * 2001-06-21 2006-07-27 Kristjan Gudmundsson Imidazo[1,2-a]pyridine derivatives for treatment of herpes viral infections
US20050228004A1 (en) * 2001-06-21 2005-10-13 Gudmundsson Kristjan S Imidazo'1,2-a!pyridine derivatives for the prophylaxis and treatment of herpes viral infections
US7186714B2 (en) 2001-06-21 2007-03-06 Smithkline Beecham Corporation Imidazo[1,2-α]pyridine derivatives for the prophylaxis and treatment of herpes viral infections
US20040214834A1 (en) * 2001-09-07 2004-10-28 Kristjan Gudmunsson Pyrazolo-pyridines for the treatment of herpes infections
US20040248917A1 (en) * 2001-10-05 2004-12-09 Kristjan Gudmundsson Imidazo-pyridine derivatives for use in the treatment of herpes viral infection
US20080139594A1 (en) * 2001-10-05 2008-06-12 Kristjan Gudmundsson Imidazo-Pyridine Derivatives For Use In The Treatment of Herpes Viral Infection
US7244740B2 (en) 2001-10-05 2007-07-17 Smithkline Beecham Corporation Imidazo-pyridine derivatives for use in the treatment of herpes viral infection
US20040248903A1 (en) * 2001-12-11 2004-12-09 Kristjan Gudmundsson Pyrazolo-pyridine derivatives as antiherpes agents
US7199120B2 (en) 2001-12-11 2007-04-03 Smithkline Beecham Corporation Pyrazolo-pyridine derivatives as antiherpes agents
US20070161653A1 (en) * 2001-12-11 2007-07-12 Kristjan Gudmundsson Pyrazolo-Pyridine Derivatives As Antiherpes Agents
US20040021778A1 (en) * 2002-08-05 2004-02-05 Oldani Jerome L. Security system with remote access and control
US7381725B2 (en) * 2002-08-13 2008-06-03 Merck Sharp & Dohme Ltd. Pyridazine derivatives as ligands for GABA receptors
US20060148809A1 (en) * 2002-08-13 2006-07-06 Fletcher Stephen R Pyridazine derivatives as ligands for gaba receptors
US20070112014A1 (en) * 2002-10-03 2007-05-17 Gudmundsson Kristjan S Therapeutic Compounds Based on Pyrazolopyridine
US7153863B2 (en) 2002-10-03 2006-12-26 Smithkline Beecham Corporation Therapeutic compounds based on pyrazolopyridline derivatives
US20050282842A1 (en) * 2002-10-03 2005-12-22 Gudmundsson Kristjan S Therapeutic compounds based on pyrazolopyridine derivatives
US20090318437A1 (en) * 2006-06-06 2009-12-24 Gaeta Federico C A SUBSTITUTED PYRAZOLO[1,5-a] PYRIDINE COMPOUNDS AND THEIR METHODS OF USE
US8431603B2 (en) 2008-04-15 2013-04-30 Eisai R&D Management Co., Ltd. 3-phenylpyrazolo[5,1-b]thiazole compounds
US20110086898A1 (en) * 2009-10-08 2011-04-14 Eisai R&D Management Co., Ltd. Pyrazolooxazole compound
US20110086882A1 (en) * 2009-10-08 2011-04-14 Eisai R&D Management Co., Ltd. Pyrazolothiazole compound
US8530504B2 (en) 2009-10-08 2013-09-10 Eisai R&D Management Co., Ltd. Pyrazolothiazole compound
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RU2570426C2 (ru) * 2009-12-18 2015-12-10 Мицубиси Танабе Фарма Корпорейшн Новое антитромботическое средство
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US9572528B1 (en) 2012-08-06 2017-02-21 Los Angeles Biomedical Research Insitute at Harbor-UCLA Medical Center Monitor for SIDS research and prevention
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AU628913B2 (en) 1992-09-24
CN1031570C (zh) 1996-04-17
EP0379979A1 (en) 1990-08-01
DE69030206T2 (de) 1997-07-10
ATE150462T1 (de) 1997-04-15
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HU211684A9 (en) 1995-12-28
HU900228D0 (en) 1990-03-28
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FI96205C (fi) 1996-05-27
AU4869690A (en) 1990-07-26
KR0159502B1 (ko) 1998-12-01
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UA43821C2 (uk) 2002-01-15
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NO900306D0 (no) 1990-01-22
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